Cells of the diffuse neuroendocrine system have storage secretory granules that ubiquitously contain the pro-hormone Chromogranin A (CHGA). CHGA is processed into peptides that are modulators of homeostasis of blood pressure, cardiac function and glucose metabolism. Paradoxically, the CHGA level is elevated in plasma of hypertensive individuals, whereas its catestatin (CST) fragment is diminished. CST is a hormone derivative of CHGA that functions as a catecholamine secretory inhibitor. The CHGA locus in humans has common genetic variations that result in inter- individual differences in biosynthesis, processing, release and other in vivo functions of CHGA. The general population has variation in both CHGA and CST levels, as well as in the primary sequence of CST. About 4.5% of the population has the variant Gly364Ser CST peptide. This study will delineate the underlying mechanism by which the elevated levels of CHGA result in diminished CST, eventuating into hypertensive state. It will also evaluate in vivo functional significance of the amino acid replacements in the CST peptide. Cardiac functions such as heart rate and its variability, baroreceptor sensitivity and peripheral blood vessel distensibility are expected to be affected by this variation in CST sequence and will be evaluated. Novel transgenic mouse models 'humanized' for the chromogranin A locus will be used to address the goals of this study. Mouse models have been created to express the human CHGA gene (wild-type and the catestatin variant), under regulation of the native human elements. This is a unique in vivo approach to study the relevance of single nucleotide polymorphisms in the catestatin hormone allowing validation of in vitro findings, observations in the human population and provides means for testing not possible in humans. The study will unravel the genetic underpinnings of CHGA-induced hypertension on cardiac autonomic control. We anticipate that the results will be of general interest to a wide audience: cardiologists, vascular biologists, neurologists, neurobiologists, endocrinologists, physiologists and pharmacologists, as well as complex trait geneticists probing genes that influence autonomic function in humans. PUBLIC HEALTH RELEVANCE: The prohormone chromogranin A, is processed into the catecholamine release antagonist catestatin with a role in regulating blood pressure. Elevated levels of this protein are observed in hypertensive individuals. This study will delineate the cause and effects of aberration in circulating levels, and polymorphisms of catestatin in hypertension.